2-substituted estra-1,3,5(10)-triene-3-yl sulfamate with an anti-tumour action

ABSTRACT

Disclosed are compounds of formula I 
                         
and use thereof in a method of treating a tumor disease that can be influenced positively by the inhibition of tubulin polymerization.

This application is a 371 of PCT/EP 04/01606 filed on Feb. 19, 2004, andclaims priority to DE 10307104.0 filed on Feb. 19, 2003.

This invention relates to 2-substituted estra-1,3,5(10)-trien-3-ylsulfamates and their use for the production of pharmaceutical agentsthat have an antitumor-active activity.

Microtubuli are organelles that occur in most eukaryotic cells and takeover a number of functions there such as mitosis, intracellularmovements, cell migration and the manifestation of the cell shape.Microtubuli are polymers that consist of tubulin, which in turnrepresents a dimer that consists of an α-unit and a β-unit. Theseheterodimers bind two guanosine triphosphate (GTP) molecules, wherebyone of the GTPs is securely bonded and the other is replaceable. In ahead-tail arrangement, the heterodimers polymerize into thread-shapedmacromolecules, the so-called protofilaments, which in turn pile up intotubular organelles, the microtubuli. Microtubuli are subject to aconstant build-up and degradation. The equilibrium between growth anddegradation depends on the availability of new GTP-tubulin subunits andthe rate of hydrolysis of the second bonded GTPs. On the plus end, newsubunits are cultivated; conversely, on the minus end, subunits diffuseoutward. It is known that cytotoxic substances such as colchicine,vinblastine, vincristine, taxol, epothilone, podophyllotoxin,steganicin, combretastatin and 2-methoxyestradiol influence the build-upor degradation of mictrotubuli (tubulin polymerization and tubulindepolymerization) and thus are able to influence the cell division in aphase-specific manner. This relates primarily to quick-growing,neoplastic cells, whose growth is largely unaffected by intracellularregulating mechanisms. Active ingredients of this type are in principlesuitable for treating malignant tumors.

Fotsis et al. Nature 1994 368, 237-239 report, moreover, that2-methoxyestradiol inhibits the tumor growth and the angiogenesis.

Cushman et al. J. Med. Chem. 1995 38, 2041-2049 examine the cytotoxicaction as well as the tubulin-polymerization-inhibiting action of2-methoxyestradiol, and report in J. Med. Chem. 1997, 40, 2323-2334,moreover, that 2-alkoxy-6-oximinoestradiol derivatives inhibit thetubulin polymerization as well as the bond of [³H]-colchicine totubulin. The 2-alkoxy-6-oximinoestradiol derivatives that are mentionedhere show comparable activity, relative to the inhibition of tubulinpolymerization, such as 2-ethoxyestradiol, which has a higher activitythan 2-methoxyestradiol.

In contrast, steroid-3-sulfamates are described in the literature asinhibitors of steroid sulfatase:

WO 93/05064 relates to, i.a., compounds of formula

whereby R¹ and R², in each case independently of one another, meanhydrogen or a methyl group, provided that at least one of radicals R¹and R² is an H atom, and the radical-O-polycyclic compound is a3-sterol, whose sulfate ester can be hydrolyzed by an enzyme withsteroid-sulfatase activity. Compounds that are substituted specificallyin the 2-position of the steroid skeleton are not explicitly disclosed.

U.S. Pat. No. 6,011,024 is based on WO 93/05064 and covers, e.g., allcompounds in which the primary sulfamate function is bonded to asix-membered ring. Compounds that are specifically substituted in the2-position of the steroid skeleton are in turn not explicitly disclosed.

WO 96/05216 relates to C2-unsubstituted estra-1,3,5(10)-triene-sulfamatederivatives.

WO 96/05217 relates to pharmaceutical compositions that contain activeingredients of general formula

in which R=NH₂; R³=C₁₋₅-alkoxy group, OH; R⁸, R⁹ and R¹⁰, independentlyof one another, ═H, OH; R⁹ and R¹⁰ together can have the meaning=0. Thepharmaceutical compositions that are disclosed therein can be used forfemale birth control; menopausal HRT and for treatment of gynecologicaland andrological images of disease, such as breast cancer or prostatecancer.

WO 97/14712 relates to steroid sulfamate derivatives of general formula

in which R¹ can represent an acyl, alkoxycarbonyl, aminocarbonyl,sulfonyl or sulfonamidyl group; R² can represent a hydrogen atom or ametal atom; R⁷ and R⁸, independently of one another, can represent H, OHand C₁₋₅-alkoxy; R¹³, R¹² and R¹¹, independently of one another, canrepresent H or OH.

WO 98/42729 relates to 16-halogen-substituted1,3,5(10)-triene-3-monosulfamates as well as 3,17β-bissulfamates, whichcan be alkoxy-substituted at C2. The 16-halogen substitution increasesboth the sulfatase-inhibiting action and the estrogeneity of thecorresponding sulfamate derivatives.

The introduction of a 17-sulfamate function in addition to the3-sulfamate function drastically reduces the estrogeneity.

WO 98/24802 relates to sulfamates that inhibit the estrone sulfatase.2-Methoxyestrone sulfamate is explicitly mentioned. As a potentialtherapeutic application, breast cancer, but not prostate cancer, ismentioned in the description.

Also, WO 99/33858 describes estrone sulfatase inhibitors of formula

in which R¹ and R², independently of one another, represent H, alkyl, ortogether piperidine, morpholine, piperazine; R³=H, CN, NO₂, CO₂R⁴; R⁸=H,NO₂, NR⁶R⁷, In the description, breast cancer is mentioned as a possibletherapeutic application.

WO 99/64013 relates to a pharmaceutical composition of a sulfamatederivative with a cell signal modifier (such as, e.g., TNFα).2-Methoxyestrone sulfamate is explicitly claimed as a preferredsulfamate in this combination; but numerous other steroid-3-sulfamatesfall under the scope of the general formula. As a mechanism of actionfor the pharmaceutical compositions according to the invention or forthe steroid-3-sulfamates contained therein (preferably with at least one2-alkoxy substituent), 1) inhibition of glucose absorption in tumorcells, 2) inhibition of tumor angiogenesis, 3) degradation ofmicrotubuli; 4) inducing of apoptosis are described. WO 00/76487 relatesto substances that inhibit the TNFα-induced aromatase activity. As such,2-alkoxyestrone-3-sulfamates, preferably 2-methoxyestrone sulfamate, areclaimed.

WO 01/18028 describes non-estrogenic estrone sulfatase-inhibitingN-acyl-18a-substituted steroid-3-sulfamates, such as, e.g.,16α-fluoro-2-methoxy-18a-homoestradiol-(N-acetylsulfamate) or16α-fluoro-2-methoxy-18a-homoestrone-(N-acetylsulfamate).

In Cancer 2000, 85, 983-994, the 2-methoxyestradiol, docetaxel andpaclitaxel-induced apoptosis in hepatoma cells and their correlationwith reactive oxygen species are compared.

Potter et al. Int. J. Cancer 2000, 85, 584-589 examine the action of2-methoxyestrone sulfamate in comparison to 2-methoxyestrone on thegrowth of breast cancer cells and induced breast tumors and find that2-methoxyestrone sulfamate has a significant therapeutic potential fortreating breast cancer.

Potter et al. Molecular and Cellular Endocrinology 2000, 160, 61-66examine the inhibition of deoxyglucose absorption in MCF-7 breast cancercells by 2-methoxyestrone and 2-methoxyestrone-3-sulfamate, whichinhibit glucose absorption by 25 to 49% with 10 μm (also2-methoxyestradiol and 2-methoxyestrone), and it follows that thecompounds could have therapeutic potential for inhibiting breast cancerby their capacity to inhibit glucose absorption.

Potter et al. Cancer Research 2000, 60, 5441-5450 describe2-methoxyestrone-sulfamate and 2-ethoxyestrone sulfamate as newantimicrotubulin-active compounds that have in-vitro anti-canceractivity in breast cancer cells and therefore also optionally could beactive in vivo. In J. Steroid Biochem. and Mol. Biol. 1999, 69, 227-238,it is reported that the inhibition of the steroid sulfatase activity isan important starting point in the treatment of hormone-dependent breastcancer. 2-Methoxyestrone sulfamate, 17-deoxyestrone sulfamate andestrone sulfamate are cited explicitly. Monocyclic or bicyclic,non-steroidal sulfamates namely inhibit the steroid sulfatase, but notas effectively as the corresponding steroid derivatives.

The object of this invention consists in making available additionalcompounds that effectively inhibit tubulin polymerization.

The object of this invention is therefore achieved according to theinvention by the use of 2-substituted estra-1,3,5(10)-trien-3-ylsulfamates of general formula I for the production of a pharmaceuticalagent:

in which the radicals R1 and R2, R6 and R7, R14 and R15, R16 and R17 aswell as R18 have the following meaning:

-   -   R¹ represents a hydrogen, C₁-C₅-alkyl or C₁-C₅-acyl,    -   R² represents C₁-C₅-alkoxy, C₁-C₅-alkyl, or a radical        —O—C_(n)F_(m)H_(o), whereby n=1, 2, 3, 4, 5 or 6, m>1 and        m+o=2n+1,    -   if R² is an alkyl, R¹⁷ can be C₁-C₅-alkoxy,    -   R⁶ represents hydrogen,    -   R⁷ represents hydrogen, hydroxy; amino, acylamino,    -   if R⁶ and R⁷ are not hydrogen, then R¹⁷ can be C₁-C₅-alkoxy,    -   or    -   R⁶ and R⁷ together represent oxygen, oxime or        O(C₁-C₅-alkyl)-oxime,    -   R¹⁴ and R¹⁵ in each case can mean hydrogen or together a        methylene group or an additional bond,    -   R¹⁶ can mean hydrogen, C₁-C₅-alkyl, or fluorine,    -   R¹⁷ can mean hydrogen, fluorine, or,    -   if R¹⁶ is a hydrogen, R¹⁷ can be a group CHXY, in which X stands        for a hydrogen atom, a fluorine, an alkyl radial with 1 to 4        carbon atoms, and Y stands for a hydrogen atom or a fluorine,        whereby        -   if X is a fluorine, Y is a hydrogen or fluorine, and        -   if X is a hydroxy, Y can only be hydrogen or        -   X and Y together can be oxygen, or    -   if R¹⁶ is a fluorine, R¹⁷ can be a hydrogen or a fluorine, or    -   R¹⁶ and R¹⁷ together can mean a group ═CAB, whereby A and B,        independently of one another, can mean hydrogen, fluorine or a        C₁-C₅-alkyl group,    -   R¹⁸ can be a hydrogen atom, or a methyl group,    -   if R¹⁸ is a methyl group, R¹⁷ can be sulfamate SO₃ NHR¹,

whereby in the B- and D-ring of the steroid skeleton, the dotted linescan also be up to two double bonds,

as well as their pharmaceutically acceptable salts.

In addition, this invention comprises the new substances aspharmaceutical active ingredients, their production, their therapeuticapplication and the pharmaceutical dispensing forms that contain the newsubstances.

The compounds of general formula (I) according to the invention or theirpharmaceutically acceptable salts can be used for the production of apharmaceutical agent for treating tumor diseases that can be influencedpositively by the inhibition of tubulin polymerization.

It was determined that the 2-substituted estra-1,3,5(10)-trien-3-ylsulfamates according to the invention more greatly inhibit in vitro thetubulin polymerization, surprisingly enough, than 2-methoxyestradiolitself. The compounds according to the invention inhibit theproliferation of tumor cells and also show in-vivo antitumor action.Moreover, the compounds according to the invention have good oralbioavailability.

Alkyl radicals are defined as straight-chain or branched-chain,saturated or unsaturated alkyl radicals. As representatives ofstraight-chain or branched-chain alkyl groups with 1-5 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, 1-ethylpropyl, 1-methylbutyl, 1,1-dimethylpropyl,2-methyl-butyl, 1,2-dimethylpropyl, 3-methylbutyl, 2,2-dimethylpropylcan be mentioned.

For example, allyl, vinyl, propenyl, butenyl, but also ethinyl, propinylor butinyl stand for unsaturated alkyl radicals.

Acyl radicals mean, for example, formyl, acetyl, propionyl, butyryl,iso-butyryl or valeryl.

A methoxy, ethoxy, n-propoxy, iso-propoxy, n-, iso-, or tert-butoxy, orpentoxy group can stand for a C₁-C₅-alkoxy radical.

Preferred according to this invention is the use of those compounds ofgeneral formula I, in which:

-   -   R¹ represents hydrogen or C₁-C₅-acyl,    -   R² represents methoxy, ethoxy or 2,2,2-trifluoroethoxy,    -   R⁶ and R⁷ in each case represent hydrogen or together oxime,    -   R¹⁴ and R¹⁵ in each case represent H or together a methylene        group,    -   R¹⁶ represents hydrogen, or fluorine,    -   R¹⁷ represents hydrogen, fluorine, methyl, difluoromethyl,        carbaldehyde, vinyl methylene, oximino, hydroxy methyl or    -   R¹⁶ and R¹⁷ together represent methylene, difluoromethylene or        monofluoromethylene,    -   R¹⁸ represents hydrogen, or methyl,

whereby in the B- and D-ring of the steroid skeleton, the dotted linescan also be an 8,9-double bond or a 16,17-double bond.

According to the invention, using separately the compounds that arementioned below is especially preferred.

-   -   1) 2-Methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (1)    -   2) 2-Methoxy-estra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate    -   3) 2-Methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl sulfamate    -   4) 2-Methoxy-estra-1,3,5(10),16-tetraen-3-yl sulfamate    -   5) 2-Methoxy-17-(E-vinyl)methylene-estra-1,3,5(10)-trien-3-yl        sulfamate (2b)    -   6) 2-Ethyl-17β-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (3)    -   7) 2-Methoxy-17(20)-methylene-estra-1,3,5(10)-trien-3-yl        sulfamate (4)    -   8) 2-Methoxy-17β-methyl-estra-1,3,5(10)-trien-3-yl sulfamate (5)    -   9) 2-Methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)trien-3-yl        sulfamate (6)    -   10)        2-Methoxy-17(20)-methylene-6-oximino-estra-1,3,5(10)-trien-3-yl        sulfamate (7)    -   11)        17(20)-Difluoromethylene-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate (8)    -   12) 17β-Difluoromethyl-2-methoxy-estra-1,3,5(10)trien-3-yl        sulfamate (9)    -   13) 2-Methoxy-estra-1,3,5(10)-14-tetraen-3-yl sulfamate    -   14) 17-Difluoro-2-methoxy-estra-1,3,5(10)-14-tetraen-3-yl        sulfamate    -   15)        17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10),14-tetraen-3-yl        sulfamate    -   16) 17β-Carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate (10)    -   17)        17β-Carbaldehyde-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   18) 17β-Hydroxymethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate (11)    -   19) 2,17β-Dimethoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   20)        17β-Ethoxy-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   21) 2-Methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate        (12)    -   22) 2-Methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (13)    -   23)        2-Methoxy-6-(O-methyloximino)-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (14)    -   24) 6α-Acetylamino-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   25) 6α-Hydroxy-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate (15)    -   26) 17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate        (16)    -   27) 17β-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   28) 17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   29) 17-Difluoro-2-methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl        sulfamate    -   30) 17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   31)        17-Difluoro-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   32) 17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   33) 2-Methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-yl        sulfamate (17)    -   34) 17α-Allyl-17β-hydroxy-2-methoxy-estra-1,3,5(10)trien-3-yl        sulfamate (2a)

Subjects of this invention are, moreover, 2-substitutedestra-1,3,5(10)-trien-3-yl sulfamates of general formula I,

in which radicals R1 and R2, R6 and R7, R14 and R15, R16 and R17 as wellas R18 have the following meaning:

-   -   R¹ represents a hydrogen, C₁-C₅-alkyl or C₁-C₅-acyl,    -   R² represents C₁-C₅-alkoxy, C₁-C₅-alkyl or a radical        —O—C_(n)F_(m)H_(o), whereby n=1, 2, 3, 4, 5 or 6, m>1 and        m+o=2n+1,    -   if R² is an alkyl, R¹⁷ can be C₁-C₅-alkoxy,    -   R⁶ represents hydrogen,    -   R⁷ represents hydrogen, hydroxy, amino, acylamino,    -   if R⁶ and R⁷ are not hydrogen, then R¹⁷ can be C₁-C₅-alkoxy,    -   or    -   R⁶ and R⁷ together represent oxygen, oxime or        O(C₁-C₅-alkyl)-oxime,    -   R¹⁴ and R¹⁵ in each case can mean hydrogen or together a        methylene group,    -   R¹⁶ can mean hydrogen, C₁-C₅-alkyl, or fluorine,    -   R¹⁷ can mean hydrogen, fluorine, or    -   If R¹⁶ is a hydrogen, R¹⁷ can be a group CHXY, in which X stands        for a hydrogen atom, a fluorine, an alkyl radical with 1 to 4        carbon atoms, and        -   Y stands for a hydrogen atom or a fluorine, whereby        -   if X is a fluorine, Y is a hydrogen or fluorine, and        -   if X is a hydroxy, Y can only be hydrogen or        -   X and Y together can be oxygen, or    -   if R¹⁶ is a fluorine, R¹⁷ can be a hydrogen or a fluorine, or    -   R¹⁶ and R¹⁷ together can mean a group ═CAB, whereby A and B,        independently of one another, can mean hydrogen, fluorine or a        C₁-C₅-alkyl group,    -   R¹⁸ can be a hydrogen atom, or a methyl group,

whereby in the B- and D-ring of the steroid skeleton, the dotted linescan also be up to two double bonds,

as well as their pharmaceutically acceptable salts.

The different alkyl, unsaturated alkyl, acyl and alkoxyl radicalscorrespond to those that are listed for the use according to theinvention.

Substituents that are also preferred in the compounds correspond tothose that are mentioned in the use according to the invention.

The compounds that are mentioned below are especially preferredaccording to the invention:

-   -   1) 2-Methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   2) 2-Methoxy-estra-1,3,5(10)-trien-3-yl (N-acetyl)-sulfamate    -   3) 2-Methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl sulfamate    -   4) 2-Methoxy-estra-1,3,5(10),16-tetraen-3-yl sulfamate    -   5) 2-Methoxy-17-(E-vinyl)methylene-estra-1,3,5(10)-trien-3-yl        sulfamate    -   6) 2-Ethyl-17β-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   7) 2-Methoxy-17(20)-methylene-estra-1,3,5(10)-trien-3-yl        sulfamate    -   8) 2-Methoxy-17β-methyl-estra-1,3,5(10)-trien-3-yl sulfamate    -   9) 2-Methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)-trien-3-yl        sulfamate    -   10)        2-Methoxy-17(20)-methylene-6-oximino-estra-1,3,5(10)-trien-3-yl        sulfamate    -   11)        17(20)-Difluoromethylene-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate    -   12) 17β-Difluoromethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate    -   13) 17β-Carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate    -   14)        17β-Carbaldehyde-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   15) 17β-Hydroxymethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl        sulfamate    -   16) 2,17β-Dimethoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   17)        17β-Ethoxy-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   18) 2-Methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate    -   19) 2-Methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   20)        2-Methoxy-6-(O-methyloximino)-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   21) 6α-Acetylamino-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   22) 6α-Hydroxy-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   23) 17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   24) 17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   25) 17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate    -   26) 17-Difluoro-2-methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl        sulfamate    -   27) 17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   28)        17-Difluoro-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl        sulfamate    -   29) 17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl        (N-acetyl)-sulfamate    -   30) 2-Methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-yl        sulfamate    -   31) 17α-Allyl-17β-hydroxy-2-methoxy-estra-1,3,5(10)trien-3-yl        sulfamate (2a)        Pharmacological Data        1. Inhibition of Tubulin Polymerization

The compounds according to the invention were tested in various models.

The compounds of general formula I according to the invention aredistinguished in that they more greatly inhibit tubulin polymerizationthan 2-methoxyestradiol. The in-vitro testing of the tubulinpolymerization influence was performed as follows:

According to Shelanski et al. (Shelanski et al. Proc. Natl. Acad. Sci.USA 1973, 70, 765-8), microtubular protein was purified from pig brainsvia cyclic assembling/disassembling. The buffer system used had thefollowing composition: 20 mmol of PIPES(1,4-piperazine-diethane-sulfonic acid, pKa 6.8), 80 mmol of NaCl, 0.5mmol of MgCl₂, 1 mmol of EGTA (ethyleneglycol-bis-(2-aminoethylene)-tetraacetic acid).

For active ingredient testing, protein concentrations of 1 mg/ml (about10⁻⁵ mmol of tubulin) were used. The determination of protein wascarried out according to the Lowry Method (Lowry et al. J. Biol. Chem.1951, 193, 265-75) with bovine serum albumin as a standard. Theassembling of microtubuli was carried out in the presence of 0.25 mmolof GTP and heating the samples to 37° C.

The microtubulus formation was examined by means of turbidimetry at awavelength of 340 nm. The state of equilibrium, in which themicrotubular protein exhibits no increase in the assemblateconcentration (corresponding to the microtubulus concentration) and theturbidity value no longer exhibits an increase, is typically reachedafter 20 minutes.

Testing of the active ingredients was carried out by their addition atthe beginning of the assembling or in the state of equilibrium.Deviations of turbidity curves from the control characterize itsactivity. To monitor action and to evaluate the measured turbidityvalues, a transmission electron microscopic study (CEM 902 A,Zeiss/Oberkochen) of the assemblates was always performed after negativestaining with 1% aqueous uranyl acetate.

TABLE 1 Inhibition of Tubulin Polymerization Name IC₅₀ [μm]2-Methoxyestradiol 2.70 (1) 0.67 (4) 1.40 (3) 1.40 (9) 1.50 (8) 1.10 (5)1.302. Inhibition of Cell Proliferation

The compounds according to the invention are distinguished by a potentinhibition of cell proliferation.

Cell cultures of the following cell lines were prepared in 96-wellmicrotiter plates:

-   -   1. MaTu/ADR multidrug-resistant human breast tumor cells (Epo        GmbH Berlin), 5000 cells/well.    -   2. HCT116 human colon tumor cells (ATCC CCL-247), 3000        cells/well.    -   3. NCl-H460 human non-small-cell lung cancer cells (ATCC        HTB-177), 3000 cells/well.    -   4. DU145 human prostate tumor cells (ATCC HTB-81), 5000        cells/well.    -   5. HMVEC human primary dermal microvascular endothelial cells,        7500 cells/well.

After 24 hours of incubation in a cell culture incubator at 37° C., thecells of a microtiter plate were stained with crystal violet (referenceplate), while the cells in the test plates were incubated for 4 dayswith the test substances in the concentrations 0.1-10 μm, as well aswith the DMSO solvent by itself (solvent control). The cellproliferation was determined by staining cells with crystal violet. Theextinction of the crystal violet was determined by photometry at 595 nm.The percentage of the change in the cell number in the test plates wasdetermined after the extinction values were normalized to the referenceplate (0%) and to the solvent control (100%). The semi-maximalinhibition of the cell growth (IC50) was determined as the substanceconcentration, in which 50% of the cell number of the solvent controlswere present.

TABLE 2 Inhibition of Cell Proliferation IC50 [μm] NCl- MaTu/ Name H460HCT116 DU145 ADR HMVEC Taxol 0.004 0.004 0.004 0.4 0.004 2- 1.8 1.1 1.90.2 2.2 Methoxyes- tradiol (4) 0.18 0.18 0.18 <0.1 0.16 (1) 0.4 0.4 0.50.11 <0.1 (3) 0.18 0.18 0.18 0.12 0.16 (9) 0.22 0.3 0.4 0.11 0.2 (8)0.22 0.3 0.5 0.17 0.2 (11)  0.18 0.18 0.2 <0.1 <0.1 (7) 0.5 0.5 0.550.13 0.13Dosage

In general, satisfactory results can be expected when the daily dosescomprise a range of 5 μg to 50 mg of the compound according to theinvention per kg of body weight. In larger mammals, for example inhumans, a recommended daily dose is in the range of 10 μg to 30 mg perkg of body weight.

Suitable dosages for the compounds according to the invention are from0.005 to 50 mg per day per kg of body weight, depending on the age andconstitution of the patient, whereby the necessary daily dose can beadministered one or more times.

Based on the special depot action of the estrogen-sulfamates, thecompounds according to the invention can, however, also be administeredat greater intervals than once per day.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art, by theactive ingredient being processed with the vehicles, fillers, substancesthat influence decomposition, binding agents, moisturizing agents,lubricants, absorbing agents, diluents, flavoring correctives, coloringagents, etc., that are commonly used in galenicals and converted intothe desired form of administration. In this case, reference is made toRemington's Pharmaceutical Science, 15^(th) Edition, Mack PublishingCompany, East Pennsylvania (1980).

For oral administration, in particular tablets, coated tablets,capsules, pills, powders, granulates, lozenges, suspensions, emulsionsor solutions are suitable.

For parenteral administration, injection and infusion preparations arepossible.

For intraarticular injection, correspondingly prepared crystalsuspensions can be used.

For intramuscular injection, aqueous and oily injection solutions orsuspensions and corresponding depot preparations can be used.

For rectal administration, the new compounds can be used in the form ofsuppositories, capsules, solutions (e.g., in the form of enemas) andointments both for systemic and for local therapy.

For pulmonary administration of the new compounds, the latter can beused in the form of aerosols and inhalants.

For topical application, formulations in gels, ointments, fattyointments, creams, pastes, powders, milks and tinctures are possible.The dosage of the compounds of general formula I should be 0.01%-20% inthese preparations to achieve an adequate pharmacological action.

This invention comprises the use of the compounds of general formula Iaccording to the invention for the production of a pharmaceutical agent,in particular for treating tumor diseases that can be influencedpositively by the inhibition of tubulin polymerization.

The compounds of general formula I according to the invention arepreferably used for the production of a pharmaceutical agent fortreating tumor diseases of the male and female gonads, male and femalesex organs including the mammary glands, in particular of prostatecancer or breast cancer.

This invention also relates to pharmaceutical compositions that containat least one especially preferred compound according to the invention,optionally in the form of a pharmaceutically/pharmacologicallycompatible salt, without or together with pharmaceutically compatibleadjuvants and/or vehicles.

These pharmaceutical compositions and pharmaceutical agents can beprovided for oral, rectal, vaginal, subcutaneous, percutaneous,intravenous or intramuscular administration. In addition to commonlyused vehicles and/or diluents, they contain at least one especiallypreferred compound according to the invention.

The pharmaceutical agents of the invention are produced with commonlyused solid or liquid vehicles or diluents and the commonly usedpharmaceutical-technical adjuvants corresponding to the desired type ofadministration at a suitable dosage in a known way. The preferredpreparations consist in a dispensing form that is suitable for oraladministration. Such dispensing forms are, for example, tablets, filmtablets, coated tablets, capsules, pills, powders, solutions orsuspensions or else depot forms.

The pharmaceutical compositions that contain at least one of thecompounds according to the invention are preferably administered orally.

Parenteral preparations such as injection solutions are also considered.In addition, for example, suppositories and agents for vaginalapplication can also be mentioned as preparations.

Corresponding tablets can be obtained by, for example, mixing activeingredient with known adjuvants, for example inert diluents such asdextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosivessuch as corn starch or alginic acid, binding agents such as starch orgelatin, lubricants such as magnesium stearate or talc and/or agents forachieving a depot effect such as carboxyl polymethylene, carboxyl methylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tabletscan also consist of several layers.

Coated tablets accordingly can be produced by coating cores, which areproduced analogously to the tablets, with agents that are commonly usedin tablet coatings, for example, polyvinyl pyrrolidone or shellac, gumArabic, talc, titanium oxide, or sugar. In this case, the shell of thecoated tablets can also consist of several layers, whereby the adjuvantsthat are mentioned above in the tablets can be used.

Solutions or suspensions with the compounds of general formula Iaccording to the invention can contain additional taste-improving agentssuch as saccharine, cyclamate or sugar, as well as, e.g., flavoringsubstances such as vanilla or orange extract. In addition, they cancontain suspending adjuvants such as sodium carboxy methyl cellulose orpreservatives such as p-hydroxybenzoates.

Capsules that contain the compounds of general formula I can be producedby, for example, the compound(s) of general formula I being mixed withan inert vehicle such as lactose or sorbitol and encapsulated in gelatincapsules.

Suitable suppositories can be produced by, for example, mixing withvehicles that are provided for this purpose, such as neutral fats orpolyethylene glycol or derivatives thereof.

For therapy of prostate cancer, the compounds according to the inventioncan be administered in combination with one or more of the followingactive ingredients:

1) Antiandrogens such as CPA, flutamide, casodex, etc.

2) Gonadotrophic hormone (GnRH) agonists

3) 5α-Reductase inhibitors such as finasteride

4) Cytostatic agents

5) VEGF-kinase inhibitors

6) Antigestagens

7) Antiestrogens

8) Antisense oligonucleotides

9) EGF antibodies

10) Estrogens

Moreover, the compounds of general formula I according to the inventioncan be used for therapy and prophylaxis of other pathologic conditionsthat are not mentioned above.

The compounds of general formula I according to the invention can beproduced as described below:

General Synthesis Part

The functionalization of C-atom 2 of an estra-1,3,5(10)-trien-17-onederivative is preferably carried out by Friedel-Crafts acylation asdescribed in the literature (T. Nambara et al. Chem. Pharm. Bull. 1979,18, 474-480).

After changing the protective group in 3-position, a2-carboxy-estra-1,3,5(10)-trien-17-one is generated by Baeyer-Villigeroxidation (M. B. Smith, J. March, March's Advanced Organic Chemistry,5^(th) Edition, Wiley Sons 2001, 1417-1418 and literature cited there).The ester is saponified and converted with the corresponding alkylhalide under basic conditions into a 2-alkyl ether. Alternately, the17-ketone as known can now be reduced and etherified. The cleavage ofthe protective group in 3-position is carried out as described in theliterature (T. W. Greene, P. G. M. Wuts, Protective Groups in OrganicSynthesis, Wiley & Sons, 1999, 249-275). This process or other processesknown from the literature (P. N. Rao, J. W. Cessac, Steroids 2002, 67,1065-1070 and literature cited there) can be used according to the18a-homo derivatives.

The 2-acyl derivatives that are preferably obtained by Friedel-Craftsacylation can be converted by reduction with sodium borohydride andsubsequent hydrogenation into the corresponding 2-alkyl derivatives.

The 2-hydroxylation, starting from compounds of general formula II(R₂=H),

in which R₁₄ and R₁₅ together form a methylene bridge or which haveadditional double bonds in the steroid skeleton, is carried out byortho-metallation, whereby preferably an ether protective group (e.g.,H. E. Paaren, S. R. Duff, U.S. Pat. No. 6,448,419 and literature citedthere) or a carbamate protective group (V. Snieckus, Chem. Rev. 1990,90, 879-933) is used for R₃ as an ortho-directing protective group. Theelectrophilic substitution is carried out after 2-lithiation withtrialkyl borate and then basic oxidation with hydrogen peroxide. Theselectively obtained 2-hydroxy group can then be converted into a2-alkoxy compound in a known way (Z. Wang, M. Cushman, Synth. Commun.1998, 28, 4431) and deprived of protection. Subsequent Oppenaueroxidation (C. Djerassi, Org. React. 1951, 6, 207, S. Schwarz et al.Pharmazie [Pharmaceutics] 2001, 56, 843-849) yields the 17-ketocompounds, which can be further functionalized and reacted as known toform the sulfamates.

Starting from the 2-functionalized 17-keto derivatives, 17-oxiranes (M.Hübner, I. Noack, J. prakt. Chem. 1972, 314, 667) and from them thecorresponding 17-formyl derivatives (M. Hübner, K. Ponsold, Z. Chem.1982, 22, 186) or 17-monofluorinated methyl derivatives (B. Menzenbachet al., DE 10043846) can be produced.

The corresponding 17-oxime, 17-alkylene (so-called Wittig reaction, see,e.g., S. Schwarz et al. Pharmazie 2001, 56, 843-849),17-difluoromethylene (Wadsworth-Emmons Reaction, S. R. Piettre, L.Cabanas, Tetrahedron Lett. 1996, 37, 5881-4884), 17-deoxo, 17β-alkyl,and 17β-hydroxymethyl derivatives can also be produced from the2-functionalized derivatives (e.g., R. H. Peters et al., J. Med. Chem.1989, 32, 1642; G. E. Agoston et al. WO 02/42319) and then sulfamoylatedin 3-position.

According to Cushman et al. (J. Med. Chem. 1997, 40, 2323), thesynthesis of 6-functionalized estrogen derivatives is carried out byoxidation of the acetyl-protected estrogen derivative with chromiumtrioxide.

17-Fluorinated derivatives can be produced from the corresponding 17-oxoor 17-hydroxy derivatives with diethylamino-sulfur trifluoride (M.Hudlicky, Org. Reactions 1988, 35, 513; J. T. Welch, Fluorine inBioorganic Chemistry 1991, John Wiley, New York; S. Rozen et al.Tetrahedron Lett. 1979, 20, 1823-1826) and then sulfamoylated.

This invention is explained in more detail based on the examples below,without being limited thereto:

Production Process

General Synthesis Instructions 1 for the Production of Sulfamates

One equivalent of an estra-1,3,5(10)-triene derivative in methylenechloride is dissolved or suspended while being stirred and mixed with 5equivalents of 2,6-di-tert-butylpyridine. Then, 10 equivalents ofsulfamoyl chloride are added under argon and stirred at roomtemperature. The solution is stirred until conversion is completed (TLCmonitoring, 1-5 hours) and then mixed with water. In acid-sensitivecompounds, buffering is done in advance with about 10 equivalents oftriethylamine. The aqueous phase is extracted several times withdichloromethane or ethyl acetate. The combined organic phases are driedon sodium sulfate and concentrated by evaporation in a vacuum and thenpurified by flash chromatography.

General Synthesis Instructions 2 for Acylation of Sulfamates

One equivalent of the estra-1,3,5(10)-triene-sulfamate or bissulfamateis dissolved in pyridine and mixed with 5 equivalents of anhydride whilebeing cooled with ice (0 to 5° C.). Stirring is continued for 1 hour atroom temperature and then mixed with water. The aqueous phase isextracted several times with dichloromethane or ethyl acetate. Thecombined organic phases are washed with 6N hydrochloric acid and thenwith water and sodium chloride solution. Then, it is dried on sodiumsulfate and concentrated by evaporation in a vacuum and then purified byflash chromatography.

EXAMPLE 1 2-Methoxy-estra-1,3,5(10)-trien-3-yl Sulfamate (1)

1.48 g of 3-hydroxy-2-methoxy-estra-1,3,5(10)-triene was reacted to formthe product according to general synthesis instructions 1 and thenpurified by flash chromatography (toluene/ethyl acetate=19:1→10:1). 1.69g (89%) of 2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (1) wasobtained as an amorphous powder.

¹H-NMR (CDCl₃): δ=0.75 (s, 3H; 18-CH₃), 2.76-2.84 (m, 2H; 6-CH₂), 3.87(s, 3H; 2-OCH₃), 4.96 (s, 2H; NH₂), 6.94, 7.03 (2 s, 2H; 1-H, 4-H).

EXAMPLE 2 17α-Allyl-17β-hydroxy-2-methoxy-estra-1,3,5(10)-trien-3-ylSulfamate (2a) and2-Methoxy-17-(E-vinyl)methylene-estra-1,3,5(10)trien-3-yl Sulfamate (2b)

622 mg of 3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one was dissolvedin 35 ml of absolute tetrahydrofuran under argon and mixed at −70° C.with 20 ml of allylmagnesium bromide solution (1 M in diethyl ether).Then, it was allowed to come to room temperature and poured into aqueousammonium chloride solution after 3 hours and extracted with ethylacetate (2×). The combined organic phases were washed with saturatedcommon salt solution, dried and concentrated by evaporation in a rotaryevaporator. Flash chromatography (cyclohexane/ethyl acetate=5:1→3:1)yielded 663 mg (94%) of17α-allyl-3,17β-dihydroxy-2-methoxy-estra-1,3,5(10)-triene as colorlesscrystals.

¹H-NMR (CDCl₃): δ=0.94 (s, 3H; 18-CH₃), 3.86 (s, 3H; 2-OCH₃), 5.16-5.23(m, 1H; C═CH₂), 5.44 (s, 1H; OH), 5.96-6.06 (m, 1H; —CH═C), 6.63, 6.79(2 s, 2H; 1-H, 4-H).

104 mg of 17α-allyl-3,17β-dihydroxy-2-methoxy-estra-1,3,5(10)-triene wasreacted to form the products according to general synthesis instructions1 and then purified by flash chromatography (cyclohexane/ethylacetate=15:1→10:1→5:1). In addition to starting material and dewateredstarting material, 28 mg (22%) of17α-allyl-17β-hydroxy-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate(2a) as well as 36 mg (29%) of2-methoxy-17-(E-vinyl)methylene-estra-1,3,5(10)-trien-3-yl sulfamate(2b) were obtained as an amorphous powder.

2a: ¹H-NMR (CDCl₃): δ=0.94 (s, 3H; 18-CH₃), 2.78-2.82 (m, 2H; 6-CH₂),3.87 (s, 3H; 2-OCH₃), 5.01 (s, 2H; NH₂), 5.16-5.24 (m, 1H; C═CH₂),5.95-6.07 (m, 1H; —CH═C), 6.92, 7.03 (2 s, 2H; 1-H, 4-H).

2b: ¹H-NMR (CDCl₃): δ=0.83 (s, 3H; 18-CH₃), 2.77-2.84 (m, 2H; 6-CH₂),3.87 (s, 3H; 2-OCH₃), 4.98-5.13 (m, 4H, 22-CH₂, NH₂), 5.76 (d, ³J=10.8Hz, 1H; 20-CH═), 6.40-6.50 (m, 1H; 21-CH═), 6.94, 7.03 (2 s, 2H; 1-H,4-H)

EXAMPLE 3 2-Ethyl-17β-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (3)

362 mg of 2-acetyl-3-benzyloxy-estra-1,3,5(10)-trien-17-one wasdissolved in 150 ml of tetrahydrofuran/methanol 10/1, mixed with sodiumborohydride and stirred for 3 hours at room temperature, mixed withacetic acid and concentrated by evaporation in a rotary evaporator. Theresidue was mixed with water and extracted with dichloromethane (2×).The combined organic phases were washed with saturated sodiumbicarbonate solution, dried and concentrated by evaporation in a rotaryevaporator. The residue was dissolved in 5 ml of absolutedimethylformamide under argon, mixed with 0.32 g of sodium hydride(˜50%) and then with 1.5 ml of methyl iodide and stirred overnight atroom temperature. After the addition of water, it was extracted withethyl acetate (2×). The combined organic phases were washed with waterand then with saturated common salt solution, dried and concentrated byevaporation in a rotary evaporator. Flash chromatography (toluene/ethylacetate=60:1) yielded 301 mg (77%) of2-(1-methoxyethyl)-3-benzyloxy-17β-methoxy-estra-1,3,5(10)-triene ascolorless crystals.

290 mg of2-(1-methoxyethyl)-3-benzyloxy-17β-methoxy-estra-1,3,5(10)-triene wasdissolved in 20 ml each of ethyl acetate and dichloromethane and thenmixed with 3 drops of acetic acid and 110 mg of palladium on activatedcarbon (10%). The hydrogenation was carried out under normal pressureover 8 hours. The catalyst was filtered out, and the solution wasconcentrated by evaporation in a rotary evaporator and co-evaporatedseveral times with toluene. Flash chromatography (toluene/acetone=80:1)yielded 220 mg (98%) of2-ethyl-3-hydroxy-17β-methoxy-estra-1,3,5(10)-triene as a colorlessfoam.

¹H-NMR (CDCl₃): δ=0.79 (s, 3H; 18-CH₃), 1.22 (t, ³J=7.6 Hz, 3H; CH₃),2.59 (q, ³J=7.6 Hz, 2H; 2-CH₂Me), 2.76-2.79 (m, 2H; 6-CH₂), 3.13 (t,³J≈8.4 Hz, 1H; 17α-H), 3.38 (s, 3H; 17β-OCH₃), 4.57 (s, 1H; OH), 6.48,7.04 (2 s, 2H; 1-H, 4-H).

93 mg of 2-ethyl-3-hydroxy-17β-methoxy-estra-1,3,5(10)-triene wasreacted to form the product according to general synthesis instructions1 and then purified by flash chromatography (toluene/ethylacetate=20:1→10:1). 110 mg (94%) of2-ethyl-17β-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (3) wasobtained as colorless crystals.

¹H-NMR (CDCl₃): δ=0.78 (s, 3H; 18-CH₃), 1.22 (t, ³J≈7.6 Hz, 3H; CH₃),2.69 (q, ³J=7.6 Hz, 2H; 2-CH₂Me), 2.81-2.84 (m, 2H; 6-CH₂), 3.31 (t,³J≈8.2 Hz, 1H; 17α-H), 3.37 (s, 3H; 17β-OCH₃), 4.97 (s, 2H; NH₂), 7.07,7.18 (2 s, 2H; 1-H, 4-H).

EXAMPLE 4 2-Methoxy-17(20)-methyleneestra-1,3,5(10)-trien-3-yl Sulfamate(4)

1.6 g of sodium hydride (55%) was added to a solution that consists of11.8 g of methyltriphenyl phosphonium bromide in 50 ml of absolutedimethyl sulfoxide at room temperature. After 30 minutes, a solutionthat consists of 1.00 g of3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one in 50 ml of absolutedimethyl sulfoxide was added thereto and then heated to 70° C. After 1hour, it was cooled to room temperature, mixed with water and extractedwith diethyl ether (3×). The combined organic phases were washed withwater, dried and concentrated by evaporation in a rotary evaporator.Flash chromatography (toluene/ethyl acetate=40:1) yielded 979 mg (98%)of 3-hydroxy-2-methoxy-17(20)-methylene-estra-1,3,5(10)-triene ascolorless crystals.

¹H-NMR (CDCl₃): δ=0.83 (s, 3H; 18-CH₃), 3.86 (s, 3H; 2-OCH₃), 4.67 (t,1H; ═CH₂), 5.41 (s, 1H; 3-OH), 6.64, 6.80 (2 s, 2H; 1-H, 4-H).

100 mg of 3-hydroxy-2-methoxy-17(20)-methylene-estra-1,3,5(10)-trienewas reacted to form the product according to general synthesisinstructions 1 (base, but in excess relative to sulfamoyl chloride) andthen purified by flash chromatography (toluene/ethyl acetate=15:1→10:1).90 mg (72%) of 2-methoxy-17(20)-methylene-estra-1,3,5(10)-trien-3-ylsulfamate (4) was obtained as a colorless powder.

¹H-NMR (CDCl₃): δ=0.83 (s, 3H; 18-CH₃), 2.79-2.81 (m, 2H; 6-CH₂), 3.87(s, 3H; 2-OCH₃), 4.68 (t, ²J=1.2 Hz, 2H; 20-CH₂), 5.01 (s, 2H; NH₂),6.94, 7.03 (2 s, 2H; 1-H, 4-H).

EXAMPLE 5 2-Methoxy-17β-methyl-estra-1,3,5(10)-trien-3-yl Sulfamate (5)

108 mg of 3-hydroxy-2-methoxy-17β-methyl-estra-1,3,5(10)-triene(obtained by hydrogenation of3-hydroxy-2-methoxy-17(20)-methylene-estra-1,3,5(10)-triene) was reactedto form the product according to general synthesis instructions 1 andthen purified by flash chromatography (toluene/ethyl acetate=30:1→15:1).124 mg (91%) of 2-methoxy-17β-methyl-estra-1,3,5(10)-trien-3-ylsulfamate (5) was obtained as colorless crystals.

¹H-NMR (CDCl₃): δ=0.59 (s, 3H; 18-CH₃), 0.88 (d, ³J=7.0 Hz, 3H; 17-CH₃),2.77-2.80 (m, 2H; 6-CH₂), 3.86 (s, 3H; 2-OCH₃), 5.01 (s, 2H; NH₂), 6.93,7.02 (2 s, 2H; 1-H, 4-H).

EXAMPLE 6 2-Methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)-trien-3-ylSulfamate (6)

3-Acetoxy-2-methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)-triene wasoxidized in 6-position with chromium trioxide in acetic acid at 10° C.in a yield of 48% and then the acetyl group was cleaved offquantitatively by sodium methanolate in methanol. Sulfamoylation of 72mg of this intermediate product according to general synthesisinstructions 1 and subsequent flash chromatography (toluene/ethylacetate=5:1) yielded2-methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)-trien-3-yl sulfamate(6) in a yield of 75% as colorless crystals.

¹H-NMR (CDCl₃): δ=0.83 (s, 3H; 18-CH₃), 3.98 (s, 3H; 2-OCH₃), 4.71 (s,2H; ═CH₂), 5.23 (s, 2H; NH₂), 7.00, 7.98 (2 s, 2H; 1-H, 4-H).

EXAMPLE 72-Methoxy-17(20)-methylene-6-oximino-estra-1,3,5(10)-trien-3-ylSulfamate (7)

55 mg of 2-methoxy-17(20)-methylene-6-oxo-estra-1,3,5(10)-trien-3-ylsulfamate (6) was heated with 70 mg of hydroxylamine-hydrochloride and100 mg of sodium bicarbonate in 3 ml of methanol for 3 hours to 60° C.Then, it was cooled to room temperature, mixed with water and extractedwith ethyl acetate (3×). The combined organic phases were washed withsaturated sodium chloride solution, dried and concentrated byevaporation in a rotary evaporator. Flash chromatography(toluene/acetone=8.1→5:1) yielded 26 mg (46%) of2-methoxy-17(20)-methylene-6-oximino-estra-1,3,5(10)-trien-3-ylsulfamate (7) as a white amorphous solid as well as as by-product3-hydroxy-2-methoxy-17(20)-methylene-6-oximino-estra-1,3,5(10)-triene.

¹H-NMR (acetone-d₆): δ=0.71 (s, 3H; 18-CH₃), 3.78 (s, 3H; 2-OCH₃), 4.55(d, 2H; ═CH₂), 6.94, 7.74 (2 s, 2H; 1-H, 4-H).

EXAMPLE 8 17(20)Difluoromethylene-2-methoxy-estra-1,3,5(10)-trien-3-ylSulfamate (8)

6.4 ml of a tert-butyllithium solution (1.5 M in pentane) was added indrops at −70° C. while being stirred to a solution that consists of 1.53ml of diethyl(difluoro-methyl)phosphonate in 10 ml of absolute1,2-dimethoxyethane. After 20 minutes, a solution that consists of 733mg of 3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one in 20 ml of1,2-dimethoxyethane was added in drops thereto and then the cooling bathwas removed, and the reaction solution was stirred for another 30minutes. Then, it was refluxed for 2 hours, cooled to room temperatureand mixed with aqueous ammonium chloride solution and extracted withethyl acetate (3×). The combined organic phases were washed withsaturated common salt solution, dried and concentrated by evaporation ina rotary evaporator. Flash chromatography (cyclohexane/ethylacetate=20:1→15:1→10:1) yielded 514 mg (63%) of17(20)-difluoromethylene-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene asan amorphous solid.

¹H-NMR (CDCl₃): δ=0.92 (s, 3H; 18-CH₃), 3.86 (s, 3H; 2-OCH₃), 5.43 (s,1H; 3-OH); 6.64, 6.78 (2 s, 2H; 1-H, 4-H)-¹⁹F-NMR (CDCl₃): δ=−91.1,−96.4 (2d, ²J=68.9 Hz).

113 mg of17(20)-difluoromethylene-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene wasreacted to form the product according to general synthesis instructions1 (base, but in excess relative to sulfamoyl chloride) and then purifiedby flash chromatography (cyclohexane/ethyl acetate=3:1→2:1). 101 mg(72%) of 17(20)-difluoromethylene-2-methoxy-estra-1,3,5((10)-trien-3-ylsulfamate (8) was obtained as an amorphous powder.

¹H-NMR (CDCl₃): δ=0.93 (s, 3H; 18-CH₃), 3.88 (s, 3H; 2-OCH₃), 4.96 (s,2H; NH₂), 6.92, 7.03 (2 s, 2H; 1-H, 4-H)-¹⁹F-NMR (CDCl₃): δ=−91.9, −96.2(2d, ²J=6.89 Hz).

EXAMPLE 9 17β-Difluoromethyl-2-methoxy-estra-1,3,5(10)-trien-3-ylSulfamate (9)

200 mg of17(20)-difluoromethylene-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene wasdissolved in 10 ml of ethyl acetate and then mixed with 3 drops ofacetic acid and 70 mg of palladium on activated carbon (10%). Thehydrogenation was carried out under normal pressure overnight. Thecatalyst was filtered out, and the solution was concentrated byevaporation in a rotary evaporator and co-evaporated several times withtoluene. Flash chromatography (cyclohexane/ethyl acetate=10:1→5:1)yielded 150 mg (74%) of17β-difluoromethyl-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene as acolorless solid.

¹H-NMR (CDCl₃): δ=0.81 (s, 3H; 18-CH₃), 3.85 (s, 3H; 2-OCH₃), 5.42 (s,1H; OH), 5.73 (td, 1H; CHF₂), 6.63, 6.77 (2 s, 2H; 1-H, 4-H)-¹⁹F-NMR(CDCl₃): δ=−113.5 (ddd, ²J_(F,F)=285.6 Hz, ²J_(F,H)=57.6 Hz,³J_(F,H)=10.2 Hz), −117.9 (ddd, ²J_(F,F)=293.0 Hz, ²J_(F,H)=56.5 Hz,³J_(F,H)=12.8 Hz).

80 mg of 17β-difluoromethyl-3-hydroxy-2-methoxy-estra-1,3,5(10)-trienewas reacted to form the product according to general synthesisinstructions 1 and then purified by flash chromatography(cyclohexane/ethyl acetate=4:1). 82 mg (83%) of17β-difluoromethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (9)was obtained as colorless crystals.

¹H-NMR (CDCl₃): δ=0.81 (s, 3H; 18-CH₃), 2.79-2.82 (m, 2H; 6-CH₂), 3.87(s, 3H; 2-OCH₃), 4.95 (s, 2H; NH₂), 5.73 (td, 1H; CHF₂), 6.91, 7.03 (2s, 2H; 1-H, 4-H)-¹⁹F-NMR (CDCl₃): δ=−113.6 (ddd, ²J_(F,F)=285.6 Hz,²J_(F,H)=59.1 Hz, ³J_(F,H)=11.7 Hz), −117.9 (ddd, ²J_(F,F)=285.6 Hz,²J_(F,H)=56.1 Hz, ³J_(F,H)=12.8 Hz).

EXAMPLE 10 17β-Carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-ylSulfamate (10)

3.02 g of 3-hydroxy-2-methoxy-estra-1,3,5(10)-trien-17-one was suspendedwith 4.1 g of trimethylsulfonium iodide in 30 ml of absolutedimethylformamide. At 10° C., 3.5 g of potassium-tert-butylate was addedin portions and then slowly heated to room temperature. After 30minutes, it was poured into ice water and extracted (3×) with ethylacetate after neutralization with saturated ammonium chloride solution.The combined organic phases were washed with water and then withsaturated common salt solution, dried and concentrated by evaporation ina rotary evaporator.3-Hydroxy-2-methoxy-estra-1,3,5(10)-triene-17β-spiro-1′,2′-oxirane wasobtained in a quantitative yield (3.19 g) as colorless crystals.

¹H-NMR (CDCl₃): δ=0.93 (s, 3H; 18-CH₃), 2.65, 2.96 (2 d, ²J=4.9 Hz, 2H;oxirane-CH₂), 3.85 (s, 3H; 2-OCH₃), 5.43 (s, 1H; 3-OH), 6.64, 6.77 (2 s,2H; 1-H, 4-H).

3.19 g of3-hydroxy-2-methoxy-estra-1,3,5(10)-triene-17β-spiro-1′,2′-oxirane and 2g of sodium azide were suspended in 30 ml of ethylene glycol and heatedunder argon to 100° C. After 1.5 hours, the solution was cooled off,mixed with saturated ammonium chloride solution and extracted withdichloromethane (3×, altogether 0.25 L). The combined organic phaseswere washed with water, dried and concentrated by evaporation in arotary evaporator. After crystallization from ethyl acetate,17α-azidomethyl-3,17β-dihydroxy-2-methoxy-estra-1,3,5(10)-triene wasobtained in a quantitative yield (3.61 g) as a white solid.

¹H-NMR (DMSO-D₆): δ=0.82 (s, 3H; 18-CH₃), 3.09, 3.43 (2 d, ²J=12.5 Hz,2H; CH₂N₃), 6.45, 6.74 (2 s, 2H; 1-H, 4-H).

3.67 g of17α-azidomethyl-3,17β-dihydroxy-2-methoxy-estra-1,3,5(10)-triene wassuspended in 80 ml of dichloromethane and mixed under argon at roomtemperature with 3.7 g of triphenylphosphine. After 16 hours, a littlewater was added and it was concentrated by evaporation in a rotaryevaporator and co-evaporated several times with toluene. Flashchromatography of the residue (toluene/ethyl acetate=1:0→20:1) yielded1.95 g (62%) of an α/β-epimer mixture, from which 1.0 g of17β-carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-ol precipitated fromacetone as colorless crystals.

¹H-NMR (CDCl₃): δ=0.80 (s, 3H; 18-CH₃), 3.86 (s, 3H; 2-OCH₃), 5.07 (s,2H; NH₂), 5.43 (s, 1H; OH), 6.64, 6.77 (2 s, 2H; 1-H, 4-H), 9.80 (s, 1H;CHO).

125 mg of 17β-carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-ol wasreacted to form the product according to general synthesis instructions1 and then purified by flash chromatography (toluene/ethylacetate=10:1→4:1). 127 mg (81%) of17β-carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (10) wasobtained as colorless foam.

¹H-NMR (DMSO-d₆): δ=0.71 (s, 3H; 18-CH₃), 3.76 (s, 3H; 2-OCH³), 5.07 (s,2H; NH₂), 6.97, 6.99 (2 s, 2H; 1-H, 4-H), 7.82 (s, 2H; NH₂), 9.75 (d,³J=1.6 Hz, 1H; CHO).

EXAMPLE 11 17β-Hydroxymethyl-2-methoxy-estra-1,3,5(10)-trien-3-ylSulfamate (11)

89 mg of 17β-formyl-2-methoxy-estra-1,3,5(10)-trien-3-ol was dissolvedin 2 ml of methanol and 6 ml of tetrahydrofuran and mixed at roomtemperature with 83 mg of sodium borohydride. After 1 hour, it was mixedwith a little acetic acid and silica gel and concentrated by evaporationin a rotary evaporator. Flash chromatography (toluene/ethyl acetate=3:2)yielded 75 mg (84%) of17β-hydroxymethyl-2-methoxy-esta-1,3,5(10)-trien-3-yl sulfamate (11) ascolorless foam.

¹H-NMR (DMSO-d₆): δ=0.63 (s, 3H; 18-CH₃), 3.47-3.52 (m, 1H; CHHOH), 3.76(s, 3H; 2-OCH₃), 4.26 (d, ²J=4.7 Hz, 1H; OH), 5.07 (s, 2H; NH₂), 6.97(s, 2H; 1-H, 4-H), 7.81 (s, 2H; NH₂).

EXAMPLE 12 2-Methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl Sulfamate(12)

3-Acetoxy-2-methoxy-18a-homoestra-1,3,5(10)-triene was oxidized in6-position with chromium trioxide in acetic acid at 10° C. in a yield of71%, and then the acetyl group was cleaved off quantitatively by sodiummethanolate in methanol. Sulfamoylation of the residue that is obtainedaccording to general synthesis instructions 1 and subsequent flashchromatography (toluene/ethyl acetate=5:1) yielded2-methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate (12) in a90% yield as colorless foam.

¹H-NMR (CDCl₃): δ=0.81 (t, ³J=7.4 Hz, 3H; 18-CH₃), 2.44-2.74 (m, 2H;7-CH₂), 3.97 (s, 3H; 2-OCH₃), 5.37 (s, 2H; NH₂), 6.97, 7.95 (2 s, 2H:1-H, 4-H).

EXAMPLE 13 2-Methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-ylSulfamate (13)

61 mg of 2-methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate(12) was heated with 65 mg of hydroxylamine-hydrochloride and 78 mg ofsodium bicarbonate in 3 ml of methanol for 4 hours to 60° C. Then, itwas cooled to room temperature, mixed with water and extracted withdichloromethane (3×). The combined organic phases were dried andconcentrated by evaporation in a rotary evaporator. Flash chromatography(toluene/acetone=9:1→5:1) yielded 38 mg (60%) of2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate (13) asan amorphous solid.

¹H-NMR (acetone): δ=0.82 (t, ³J=7.4 Hz, 3H; 18-CH₃), 3.18 (dd, ²J=18.0,³J=4.3 Hz, 1H; 7-CH), 3.90 (s, 3H; 2-OCH₃), 6.96 (br s, 2H; NH₂), 7.04,7.89 (2 s, 2H; 1-H, 4-H), 10.07 (s, 1H; OH).

EXAMPLE 142-Methoxy-6-(O-methyloximino)18a-homoestra-1,3,5(10)-trien-3-ylSulfamate (14)

74 mg of 2-methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate(12) was heated with 158 mg of O-methylhydroxylamine-hydrochloride and157 mg of sodium bicarbonate in 3 ml of methanol for 3 hours to 70° C.Then, it was cooled to room temperature, mixed with water and extractedwith dichloromethane (3×). The combined organic phases were dried andconcentrated by evaporation in a rotary evaporator. Flash chromatography(toluene/acetone=14:1→9:1) yielded 59 mg (74%) of2-methoxy-6-(O-methyloximino)-18a-homoestra-1,3,5(10)-trien-3-ylsulfamate (14) as gray foam.

¹H-NMR (CDCl₃): δ=0.79 (t, ³J=7.4 Hz, 3H; 18-CH₃), 3.18 (dd, ²J=18.2,³J=4.5 Hz, 1H; 7-CH), 3.91 (s, 3H; NOCH₃), 3.95 (s, 3H; 2-OCH₃), 5.21(s, 2H; NH₂), 6.90, 7.89 (2 s, 2H; 1-H, 4-H).

EXAMPLE 15 6α-Hydroxy-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-ylSulfamate (15)

2-Methoxy-6-oxo-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate (12) wasdissolved in methanol and mixed in an ice bath with excess sodiumborohydride. The ice bath was removed, and after 2 hours, it was mixedwith acetone and concentrated by evaporation in a rotary evaporator. Theresidue was mixed with aqueous ammonium chloride solution and extractedwith dichloromethane (3×). The combined organic phases were dried andconcentrated by evaporation in a rotary evaporator. Flash chromatography(toluene/ethyl acetate=5:1→3:1) yielded about 50%6α-hydroxy-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate (15)as colorless crystals.

¹H-NMR (CDCl₃): δ=0.78 (t, ³J=7.4 Hz, 3H; 18-CH₃), 3.87 (s, 3H; 2-OCH₃),4.77 (dd, 1H; 6β-H), 5.32 (s, 2H; NH₂), 6.88, 7.44 (2 s, 2H; 1-H, 4-H).

EXAMPLE 16 17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl Sulfamate(16)

215 mg of 2-methoxy-estra-1,3,5(10)-triene-3,17β-diol was dissolved in20 ml of absolute dichloromethane and cooled to −35° C. Then, 280 μl ofdiethylamino sulfur trifluoride was added, and the cold bath wasremoved. After 1 hour, it was poured into aqueous sodium bicarbonatesolution and extracted with dichloromethane (3×). The combined organicphases were dried and concentrated by evaporation in a rotaryevaporator. Flash chromatography (cyclohexane/ethyl acetate=10:1)yielded 49% crude product, which was purified by means of HPLC (ChiracelOD-H 250×4.6 mm; n-heptane/2-propanol=95/5). 46 mg (21%) of17α-fluoro-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene was obtained ascolorless crystals.

¹H-NMR (CDCl₃): δ=0.70 (d, 3H; 18-CH₃), 3.85 (s, 3H; 2-OCH₃), 4.57 (dd,J_(H,F)=55.3, J_(H,H)=5.3 Hz, 1H; 17β-H), 5.46 (s, 1H; OH), 6.64, 6.80(2 s, 2H; 1-H, 4-H)-¹⁹F-NMR (CDCl₃): δ=−177.25 (ddd, ²J=70.4, ³J=34.6and 21.5 Hz).

34 mg of 17α-fluoro-3-hydroxy-2-methoxy-estra-1,3,5(10)-triene wasreacted to form the product according to general synthesis instructions1 and then purified by flash chromatography (toluene/ethylacetate=12:1→5:1). 42 mg (98%) of17α-fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate (16) wasobtained as an amorphous solid.

¹H-NMR (CDCl₃): δ=0.71 (d, J=1.6 Hz, 3H; 18-CH₃), 2.79-2.82 (m, 2H;6-CH₂), 3.88 (s, 3H; 2-OCH₃), 4.58 (dd, J_(H,F)=55.5, J_(H,H)=5.1 Hz,1H; 17β-H), 5.29 (s, 2H; NH₂), 6.94, 7.04 (2 s, 2H; 1-H, 4-H)-¹⁹F-NMR(CDCl₃): δ=−177.38 (ddd, ²J=70.4, ³J=34.6 and 19.9 Hz).

EXAMPLE 17 2-Methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-ylSulfamate (17)

A suspension of 570 mg of 2-methoxy-17-oxo-estra-1,3,5(10)-trien-3-ylsulfamate, 365 mg of hydroxylamine hydrochloride and 441 mg of sodiumbicarbonate in 8 ml of methanol was stirred under reflux for one hour.Then, it was mixed with 30 ml each of water and ethyl acetate. Afterphase separation, the aqueous phase was extracted twice more with 15 mleach of ethyl acetate. The combined organic phases were first washedwith 15 ml of 0.5N HCl and then with saturated NaCl solution, dried onsodium sulfate and concentrated by evaporation in a rotary evaporator.The crude product was purified by flash chromatography (toluene/ethylacetate 3:1). 444 mg (73%) of2-methoxy-(E)-17-(oximino)-estra-1,3,5(10)-trien-3-yl sulfamate (17) wasobtained as colorless crystals.

¹H-NMR (DMSO-d₆): δ=0.87 (s, 3H; 13-CH₃), 3.76 (s, 3H; 2-OCH₃), 6.98,6.99 (2 s, 2H; 1-H, 4-H), 7.82 (s, 2H; NH₂), 10.09 (s, 1H; N—OH)

1. A method of treating a tumor disease which is selected from the groupconsisting of breast cancer, prostate cancer, colon cancer,non-small-cell-lung cancer and primary dermal microvascular endothelialcell proliferation comprising administering to a subject in need thereofan effective amount of a compound of formula I

wherein R¹ is hydrogen or C₁-C₅-alkyl, R² is C₁-C₅-alkoxy, C₁-C₅-alkyl,or —O—C_(n)F_(m)H_(o), n=1,2,3,4,5 or 6, m>1, m+o=2n+1, R⁶ is hydrogen,R⁷ is hydrogen, hydroxy, amino, or acylamino, or R⁶ and R⁷ together arean oxygen, oxime or O(C₁-C₅-alkyl)-oxime group, R¹⁴ and R¹⁵ are eachhydrogen or together a methylene group or an additional bond, R¹⁶ ishydrogen, or fluorine, R¹⁷ is fluorine, or if R¹⁶ is hydrogen, R¹⁷ isalso a CHXY, X is fluorine, or hydroxyl, Y is hydrogen or fluorine, if Xis hydroxyl, Y is hydrogen, or X and Y together can be oxygen, R¹⁸ ishydrogen or methyl, wherein in the B- and D-ring of the compound offormula I, the dotted lines can be up to two double bonds, provided thatwhen a double bond is present in the D ring, only R¹⁷ is present, or apharmaceutically acceptable salt thereof.
 2. A method according to claim1, wherein R¹ is a hydrogen.
 3. A method according to claim 1, whereinR² is a methyl, ethyl, methoxy, ethoxy or 2,2,2-trifluoroethoxy.
 4. Amethod according to claim 1, wherein R⁶ and R⁷ are each a hydrogen ortogether an oxime group.
 5. A method according to claim 1, wherein R¹⁴and R¹⁵ are each an H or together a methylene group.
 6. A methodaccording to claim 1, wherein R¹⁶ is a hydrogen or fluorine.
 7. A methodaccording to claim 1, wherein R¹⁷ is a fluorine, difluoromethyl,carbaldehyde, or hydroxymethyl group.
 8. A method according to claim 1,wherein R¹⁸ is hydrogen.
 9. A method according to claim 1, wherein thecompound administered is17β-Difluoromethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-estra-1,3,5(10),14-tetraen-3-yl sulfamate;17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10),14-tetraen-3-yl sulfamate;17β-Carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17β-Carbaldehyde-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate;17β-Hydroxymethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17β-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate; or17-Difluoro-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-ylsulfamate.
 10. A method according to claim 1, which is for treatingbreast cancer.
 11. A method according to claim 1, which is for treatingprostate cancer.
 12. A method according to claim 1, which is fortreating colon cancer.
 13. A method according to claim 1, which is fortreating non-small-cell-lung cancer.
 14. A method according to claim 1,which is for treating primary dermal microvascular endothelial cellproliferation.
 15. A method according to claim 1, wherein R² isC₁-C₅-alkyl, or a radical —O—C_(n)F_(m)H_(o).
 16. A method according toclaim 1, wherein R⁷ is hydroxy, amino, or acylamino, or R⁶ and R⁷together are oxygen, oxime or O(C₁-C₅-alkyl)-oxime group.
 17. A methodaccording to claim 1, wherein R¹⁴ and R¹⁵ are together a methylenegroup.
 18. A method according to claim 1, wherein R¹⁶ or R¹⁷ isfluorine, or R¹⁷ is CHXY, wherein X is a fluorine, or a hydroxyl group,and Y is a hydrogen atom or a fluorine group.
 19. A method according toclaim 1, wherein R¹⁸ is methyl.
 20. A method according to claim 1, whichis for treating prostate cancer wherein at least one additional activeingredient is administered.
 21. A method according to claim 1, whereinthe compound administered is17β-Difluoromethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-estra-1,3,5(10),14-tetraen-3-yl sulfamate;17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10),14-tetraen-3-yl sulfamate;17β-Carbaldehyde-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17β-Carbaldehyde-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate;17β-Hydroxymethyl-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17α-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17β-Fluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-6-oximino-estra-1,3,5(10)-trien-3-yl sulfamate;17-Difluoro-2-methoxy-18a-homoestra-1,3,5(10)-trien-3-yl sulfamate; or17-Difluoro-2-methoxy-6-oximino-18a-homoestra-1,3,5(10)-trien-3-ylsulfamate or a pharmaceutically acceptable salt thereof.